Jumping Genes and the Dark Genome: MSK Researchers Gain New Insight into Childhood Cancers

By Jim Stallard,

Cartoon illustration of DNA double-helix segment (with arms and legs) “jumping” to from one part of the double-helix to another.
Summary

Researchers have found that a gene called PGBD5 plays a role in causing many pediatric cancers by creating mutations that turn cells malignant.

Cancer is primarily a disease of the aged. A person’s risk rises throughout the years as genetic mutations pile up, due either to copying mistakes when cells replicate or to ongoing exposure to certain environmental factors. Researchers have long been puzzled by why tumors develop in children, who presumably haven’t had enough time for large numbers of random mutations to accumulate.

A new study led by Memorial Sloan Kettering scientists points to a surprising cause: a gene called PGBD5 that becomes abnormally activated during childhood. An enzyme made by the gene snips out DNA segments and flips them or moves them to a different location within the genome. This DNA transfer can drastically alter normal gene function and trigger cancer.

This landmark discovery suggests a cause behind the development of solid tumors, including most types of cancer that affect children and young adults. Rather than normal cells becoming cancerous as a result of random mutations, the PGBD5 gene itself produces the mutations and turns cells malignant.

“This explains a long-standing conundrum as to how pediatric tumors develop and provides a whole new category of human cancers that result from this process,” says MSK cancer biologist and pediatric oncologist Alex Kentsis, who led the study. “We suspect similar mechanisms will be identified by future research, and their study should open new avenues of treatment.” 

The finding was published in Nature Genetics by an international collaboration of researchers.

This explains a long-standing conundrum for how pediatric tumors develop.
Alex Kentsis
Alex Kentsis cancer biologist and pediatric oncologist

The Role of the Dark Genome

PGBD5 was already understood to be a type of enzyme called a DNA transposase. A wide range of multicellular organisms use DNA transposases to control gene expression. They rearrange DNA segments known as transposons. This phenomenon was first uncovered in the 1940s and ’50s by Barbara McClintock. In her studies of corn, she revealed that DNA segments can sometimes move, or transpose, from one site on a chromosome to another. (This explains why corn can produce many colors of kernels on a single ear: The transposons alter the expression of pigment-controlling genes.) This discovery about transposons — also called “jumping genes” — and how they affect gene expression brought Dr. McClintock the Nobel Prize.

Since then, similar DNA sequences have been found in most living organisms. Although it is now known that almost 50% of the human genome is derived from transposons, very few instances of their functions are known. Rather, they were considered artifacts of evolution, lying within the “dark genome” — the portion of DNA that doesn’t code for proteins. But in recent years, scientists have come to understand that the dark genome, also referred to as junk DNA, actually serves important functions.

In particular, the RAG1/2 gene encodes a DNA transposase that is crucial for the formation of antibodies and other immune receptors that rely on the cutting and reshuffling of gene segments. But researchers thought RAG1/2 was a special case, a freak of evolution. Then in 2015, Dr. Kentsis led research revealing that PGBD5 could be active in cutting and pasting DNA in human cells. The new study shows that PGBD5, when aberrant, can induce cancer in humans.

In recent years, scientists have come to understand that the dark genome actually serves important functions.

The research team made its discovery by analyzing the genes of cells from human rhabdoid tumors. These rare childhood cancers are aggressive and can arise in many different organs, including the brain, kidneys, and liver. The scientists found evidence of DNA rearrangements at specific sites in human chromosomes associated with PGDB5 activity. As further proof of its effect, they found that expressing PGDB5 in normal human cells could turn them cancerous in both a lab dish and mouse models.

Back to top Arrow (up) icon.Icon pointing upwards. Usually means that the containing element can be opened and closed.

A Therapeutic Target

The finding solves another mystery about many childhood cancers. It is not that these cancers lack mutations but rather that they have unique genomic rearrangements. Researchers were vexed by how this genome shuffling could take place and how it might contribute to cancers that develop at an early age — many of which, like rhabdoid tumors, remain difficult to treat.

Dr. Kentsis explains that the normal function of PGBD5 is not yet clear. There are clues it may carry out essential functions in normal cells, but its role in cancer is startling.

Cancer cells in which the PGBD5 enzyme is improperly regulated may be especially reliant on DNA repair functions, says Dr. Kentsis. That could make them particularly vulnerable to drugs that inhibit specific aspects of cellular DNA repair, an especially active field of cancer research. Dr. Kentsis and colleagues are currently investigating these inhibitors in mouse models of childhood tumors in the lab.

“Despite years of sequencing and laboratory studies of childhood tumors, this is a novel mechanism of mutation that the world has missed,” says Andrew Kung, Chair of MSK’s Department of Pediatrics. “This paper represents a major advance in understanding human cancers in general and pediatric tumors in particular. And it underscores yet again that the genome still has features we are blind to that have major functions in biology that we’re just starting to appreciate.”

Back to top Arrow (up) icon.Icon pointing upwards. Usually means that the containing element can be opened and closed.

Comments

Hi,
This is a great breakthrough. My daughter was diagnosed with Stage IV ARMS in 2011. She passed in 2013. She has 4 siblings including a fraternal twin and a niece and nephew, with more to come. Should my / or is there a way for my children to be tested for this gene if they choose to be? Any insight would be most helpful. Thank you.

Dear Maryanne, we are very sorry for your loss. You may want to consult with a genetic counselor to find out if your family carries any kind of inherited risk. If you are in the New York City area and would like to speak with someone at MSK, you can call 646-888-4050 or go to https://www.mskcc.org/cancer-care/risk-assessment-screening/hereditary-… for more information. Thank you for your comment, and best wishes to you.

Please sign me up

Add new comment

We welcome your questions and comments. While we share many of them with our world-class doctors and researchers, we regret that in order to protect your privacy, we are not able to make personal medical recommendations on this forum, nor do we publish comments that contain your personal information. If you would like to consult with an MSK doctor, we encourage you to make an appointment at 800-525-2225 or request an appointment online.

Your email address is kept private and will not be shown publicly.